Cancer of the urothelium is not a single disease. It encompasses a spectrum of neoplasms ranging from a papillary growth of slow and recurrent course (low-grade carcinoma, LGCA) to a highly invasive and aggressive tumor of rapid lethality (high-grade carcinoma, HGCA). Factors responsible for these characteristics are unknown. In an attempt to uncover the causative factors, we offer the following hypotheses and propose several objectives accordingly. 1. At least 2 urinary growth factors are invovled in the development of urothelial carcinoma. They are ornithine decarboxylase (ODC)-inducible substance(s) and transferrin (TF). Urothelial cells once initiated by carcinogen become permanently responsive to the ODC-inducible substance(s), thus acquiring growth advantage over normal cells. If receptor activation constitutes a subsequent response to the ODC-inducible urinary factors. 2. The biologic aggressiveness of rat urothelial carcinoma is determined by the dose of the carcinogen (i.e. N-methyl-N- nitrosourea, MNU) and the mode of its administration, and this biological behavior is attributable to quantitative and qualitative differences in protooncogene expression. The immediate objectives are: 1) to isolate the ODC-inducible urinary components, and once they have been separated, to determine their biochemical characteristics and compare with that of rat epidermal growth factor. 2) to determine mechanisms of TF action on urothelial cells during tumor progression as well as in the fully transformed state, and 3) to examine the difference in oncogene expression between the low-grade and high-grade carcinomas induced by MNU. To achieve these goals, the heterotopically transplanted rat urinary bladder (HTB) system will be used to induce HGCA and LGCA and to test the effects of TF and ODC-inducible urinary components. Oncogene expression will be examined by using tumorigenicity assay with the NIH/3T3 cells, and by using existing available cellular/viral oncogenes as probes to determine if the activities of these oncogenes differ in these 2 types of carcinomas.